The present invention relates in general to the development, characterization and use of contrast agents used for the magnetic resonance imaging of tissue, and more particularly, to the synthesis and use of contrast agents for use during magnetic resonance imaging of samples.
Without limiting the scope of the invention, its background is described in connection with magnetic resonance imaging-based systems, as an example.
Heretofore, in this field, gadolinium complexes have been observed to enhance relaxation of water protons via rapid exchange of inner-sphere water molecules with bulk solvent. Recent kinetic results, however, have shown that the lifetime of an inner-sphere water molecule in Gd3+ complexes can range from 0.84 ns for aqueous Gd3+, 208 ns for GdDOTAxe2x88x92, to over 19000 ns in the tetraamide analog below.
Present gadolinium-based complexes, however, fail to provide 
customizable solutions to show a contrast where there is no variation in the cellular uptake of the complex. Also, presently available gadolinium-based contrast agents generally provide only an on or off signal, that is, they either cause or fail to cause a contrast. Therefore, presently available compounds are insensitive to particular biological situations and functions.
It has been found, however, that the present magnetic resonance imaging agents and methods are insensitive to changes in the environment of use. A significant problem of current systems for causing contrast during magnetic resonance imaging is that the user is completely dependent on the differential uptake of the contrast agent by the target around the region to be analyzed. It has been found that certain contrast agents are preferred due to increased uptake of the contrast agent by the target, e.g., tumors. These contrast agents work well as long as the tumor""s uptake is greater than that of the surrounding tissue. But if the uptake between the target and the surrounding tissue is similar then no contrast is observed.
Another problem with presently available contrast agents is that, the contrast agent captured by the target provides a single image of the target without regard to its metabolic condition. A contrast agent is required that can be taken up by the target, but that is also able to report on the changing metabolic status of the target vis-a-vis the surrounding tissue.
The present inventors have developed and characterized a new contrast agent for use with magnetic resonance imaging systems that has an unusual pH dependence. One such agent has increased contrast versus the surrounding medium at between pH 4 and 6, reaching a maximum near pH 6, gradually decreasing to a minimum near pH 8.5, then remaining pH insensitive to 10.5. Further characterization of the pH sensitivity and the mechanism by which this occurs was also determined, and was used to develop new agents having varying pH dependence.
More particularly, the present invention is a composition and method for making and using the same as a contrast agent during magnetic resonance imaging (MRI). A compound of the invention has the formula:
wherein R, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are made up of spacer groups and proton exchange groups such that xe2x80x94Rxe2x95x90xe2x80x94spacer group)(proton exchange group). The proton exchange groups of R and Rxe2x80x2xe2x80x3 are usually the same and are functional groups containing at least one hydrogen that is capable of hydrogen bonding with 
water. Likewise, the proton exchange groups for Rxe2x80x2 and Rxe2x80x3 are usually the same and are functional groups containing at least one hydrogen that is capable of hydrogen bonding with water, although if R and Rxe2x80x2xe2x80x3 contain functional groups with hydrogens capable of hydrogen bonding with water, some applications may require that Rxe2x80x2 and Rxe2x80x3 not have any hydrogens capable of hydrogen bonding. In one embodiment Rxe2x95x90Rxe2x80x2xe2x95x90Rxe2x80x3xe2x95x90Rxe2x80x2xe2x80x3.
More particularly, the chelating compound may have a inner-sphere water molecule lifetime of greater than 1000 ns. For use as a contrast agent in MRI the chelating compound will be used to chelate lanthanide (III) ions, preferably gadolinium ions. The water relaxivity of the compound, and particularly the proton exchange rate, is dependent upon the pH of the solution. The proton exchange group will generally have a pKa of less than 10. The spacer group may be, for example, an acetamide moiety.
The present invention is also directed to a magnetic resonance imaging contrast agent that includes a gadolinium ion and a tetraamide base complexed to the gadolinium ion having the formula: 
wherein the tetraamide base comprises four proton-exchange groups attached to each nitrogen atom of the tetraamide base, and wherein the proton-exchange groups are selected from the group consisting of phosphonates, sulfonates, carboxylates, imidazoles or acidic alcohols.
Finally, a method of increasing the contrast of magnetic resonance images of a patient is disclosed that includes; administering to a patient in need of magnetic resonance imaging a diagnostically effective amount of a tetraamide compound or a salt thereof having the formula:
wherein R, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 have a spacer group and a proton exchange group, wherein the proton exchange groups for R and Rxe2x80x2xe2x80x3 are functional groups containing a hydrogen capable of hydrogen bonding with water, and the proton exchange groups for Rxe2x80x2 and Rxe2x80x3 are the same and are functional groups containing a hydrogen capable of hydrogen bonding with water.